Stereoselective Reduction of δ‐Hydroxy‐β‐ketoesters

Abstract

The reduction of 6-hydroxy-/l-ketoesters 1 was investigated with three different reducing agents. In several instances, high selectivity in favor of syn-1.3-diols was observed.Stereoselective preparation of the 1,3-diol function has great utility in synthetic organic chemistry due to the occurrence of these fragments in several natural products. In connection with our work on compactin analogues [l], we needed an efficient and general method for preparing syn-l,3-diols.Towards this objective, we have prepared [2] a series of 6-hydroxy-P-ketoesters 1 (Scheme I ) by the addition of acetoacetate dianion to the respective aldehydes and investigated their reductions with different agents.Stereoselective reductions of 8-hydroxy-ketones utilizing metal-chelation control have recently been reported in the literature. The boron-chelate method [3], which gives excellent selectivity in favor of the syn -dials, invokes cyclic complexes 3 for explaining the stereochemical outcome of the reduction. In the alternative Zn(BH,), method [4], the setup for the reduction is presumed to be 4. At the outset of our investigations with 6-hydroxy-P-ketoesters, we were intrigued by the possibility that a simple H-bond as shown in 5 may provide a sufficiently strong bridge for achieving the desired syn-selectivity . Accordingly, we examined the hydrogenation of la2) using 5 % Pt/C (room temperature, 50 psi) in MeOH. Under these condi-') ') Present address: Ciba-Geigy AG, CH-4002 Basel. All the hydroxy-ketoesters la-k described are derived from the addition of acetoacetate dianion to the corresponding aldehydes, following [2].

Synthesis of anti‐1,3‐Diols through RuCl3/PPh3‐Mediated Hydrogenation of β‐Hydroxy Ketones: An Alternative to Organoboron Reagents

“… [c] The de values were determined by HPLC analysis. For the determination of the diastereomeric excess, an authentic sample of the anti ‐1,3‐diol 2 was obtained by reduction of 1 with Me 4 NBH(OAc) 3 ,4b while an authentic sample of the syn ‐1,3‐diol was prepared by reduction with Et 2 BOMe/NaBH 4 3b. The identities of the diastereomers were established on the corresponding acetonides by using the protocol reported by Rychnovsky 10…”

Solvent‐ and Structure‐Dependent Regioselectivity in the Boron‐Mediated Aldol Reaction of 2‐(1,3‐Dioxolan‐2‐yl)ethyl Ethyl Ketones

“…the acetonide or cyclic ketal) was impossible in our hands. The Prasad-Narasaka reduction, [17][18][19][20] or catecholborane [21] reduction, which should give the corresponding 1,3-syn-diol, were ineffective. Access to 1,3-anti-diol using Evans-Carreira [22] or Evans-Tishchenko [23] conditions was also denied.…”

“…In contrast with aldol products 21a, 24b-d and 25b-d could now be smoothly reduced to the corresponding 1,3-syn-diols. Whereas 21a required the use of catecholborane, [21] 24b-d and 25b-d reacted smoothly under Narasaka-Prasad conditions [17][18][19][20] (Scheme 8). In both cases, the corresponding acetonides 26b-d and 27b-d were obtained using standard reaction conditions.…”

Application of Chiral 2-Isoxazoline for the Synthesis of syn-1,3-Diol Analogues

“…1,2 (3R)-β-Hydroxy-δ-lactone or its open-ring equivalent (3R)-syn-3,5-dihydroxypentanoic acid, is a common structure in naturally occurring mevastatin (or compactin), lovastatin or closely related statins, and synthetic statins. Either syn-or anti-1,3-diol could be prepared from enantiomerically pure β-hydroxy ketone via β-hydroxy directed carbonyl reduction in Evans' 3 or Prasad's [4][5][6][7][8][9][10][11] method. Narasaka-Prasad reduction of the δ-hydroxy-β-keto-ester derived from a β-hydroxy ester [12][13][14][15][16][17][18][19][20][21][22][23] is widely used to prepare t-butyl (3R)-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (Scheme 1a) [24][25][26][27][28][29][30][31][32][33][34][35][36][37] , which is a building block for synthetic statins, [38][39][40][41] though enzymatic synthesis [42][43][44][45]…”